Salmonella enterica serovar Typhimurium is a common cause of enterocolitis in humans and cattle but causes a systemic, typhoid-like, disease in susceptible mice. Pathogenesis of this facultative intracellular pathogen is dependent on the ability to invade non-phagocytic cells, such as those found in the intestinal epithelium. Invasion is dependent on a type III secretion system (T3SS1), which is used to translocate a set of bacterial effector proteins into the host cell. Following internalization intracellular Salmonella survive and replicate within a modified phagosome, the Salmonella-containing vacuole (SCV). A second type III system (T3SS2) is induced intracellularly and is associated with intracellular survival/replication and biogenesis of the SCV. To understand Salmonella pathogenesis we must dissect the roles of the individual T3SS1 and T3SS2 effector proteins as well as the mechanisms that control their expression and activity inside host cells. The T3SS1 effector SopB/SigD, is an inositol phosphatase that is involved in uptake but also induces the activation of mammalian serine threonine kinase Akt/PKB and can prevent the onset of apoptosis in epithelial cells. In contrast, to SopB the roles of the T3SS2 effectors PipB and PipB2 remain obtuse. While sharing significant homology these effectors appear to have distinct functions, since they have distinct intracellular localizations and, whereas PipB is required for the cecal colonization of chicks and the induction of secretory and inflammatory responses in bovine ligated ileal loops, PipB2 is required for virulence in a mouse model. To determine the roles of these effectors in pathogenesis we are carrying out comprehensive analysis of their localization, function and regulation in infected human cells.